Granulocyte colony-stimulating factor enhances host defenses against bacterial pneumonia following peritonitis in nonneutropenic rats*

Objective: Polymorphonuclear cell functions frequently are impaired in critically ill patients, and restoration of normal functions could help to prevent nosocomial infections. The aim of this study was to evaluate the effects of pretreatment with granulocyte colony-stimulating factor (G-CSF) on bacterial pneumonia induced 48 hrs after peritonitis (cecal ligation and puncture [CLP]) in rats. Design: Controlled animal study. Setting: Research laboratory of an academic institution. Subjects: Male Sprague-Dawley rats. Interventions: First, the CLP model was characterized. Second, alveolar endotoxin instillation allowed us to evaluate the ability of neutrophils to migrate to airspaces after CLP was assessed. In the last set of experiments, CLP was followed by G-CSF treatment as a preventive therapy for subsequent bacterial superinfection induced by alveolar Pseudomonas aeruginosa instillation. Measurements and Main Results: CLP induced a brief increase in proinflammatory cytokines (tumor necrosis factor-α, interleukin-1β) at the 6th hr followed by a longer-lived anti-inflammatory response (interleukin-10 increase from days 1 to 3) in plasma, compared with healthy rats. Impaired neutrophil migration to alveolar spaces denoting immunoparalysis was evidenced after endotracheal endotoxin instillation following CLP, compared with non-CLP rats challenged with endotoxin. No such impairment was found when G-CSF (100 μg/kg: glycosylated recombinant human G-CSF, Lenograstim) was given before endotoxin. G-CSF (100 μg/kg 24 and 48 hrs after CLP) given before endotracheal P. aeruginosa instillation increased bacterial clearance, as shown by P. aeruginosa counts in both bronchoalveolar lavage (8.9 x 10 3 ± 2.8 x 10 3 colony-forming units/mL vs. 3.3 x 10 4 ± 1.5 x 104 colony-forming units/mL with saline) and lung tissue (4.2 x 105 ± 1.0 x 105 colony-forming units/g vs. 1.5 x 10 6 ± 0.6 x 10 6 colony-forming units/g with saline). Furthermore, G-CSF pretreatment kept P. aeruginosa clearance in CLP rats similar to that in non-CLP rats challenged with P. aeruginosa. Conclusion: These results suggest that G-CSF (Lenograstim) may enhance host defenses in rats with peritonitis and immunoparalysis.